Circulating Interleukins and Risk of Multiple Sclerosis: A Mendelian Randomization Study

Lu, Hui; Wu, Pengfei; Zhang, Wan; Liao, Xiaoyao

doi:10.3389/fimmu.2021.647588

Cited by 20 publications

(8 citation statements)

References 44 publications

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“…In the present study, we first found evidence that peripheral leucocyte and lymphocyte counts were positively associated with the risk for MS using summary statistics from a recent large scale GWAS analyzing blood cell traits. This is in line with some recent MR studies, which indicate a causal relation between circulating interleukins (ILs) and MS ( 36 ), and that the association between BMI and MS is partly mediated via IL-6 signaling ( 37 ). Considering that the regulatory effects of variants are often dependent on cellular subtypes, it is to be expected that deciphering their pathologic roles will require analyzing the disease-relevant cell types ( 6 , 38 ).…”

Section: Discussionsupporting

confidence: 91%

The Effect of Peripheral Immune Cell Counts on the Risk of Multiple Sclerosis: A Mendelian Randomization Study

Liu

Shen

et al. 2022

Front. Immunol.

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ObjectivesMultiple sclerosis (MS) is a complex central nervous system (CNS) demyelinating disease, the etiology of which involves the interplay between genetic and environmental factors. We aimed to determine whether genetically predicted peripheral immune cell counts may have a causal effect on MS.MethodsWe used genetic variants strongly associated with cell counts of circulating leukocyte, lymphocyte, monocyte, neutrophil, eosinophil, and basophil, in addition to some subpopulations of T and B lymphocyte, as instrumental variables (IVs) to perform Mendelian randomization (MR) analyses. The effect of immune cell counts on MS risk was measured using the summary statistics from the International Multiple Sclerosis Genetics Consortium (IMSGC) genome-wide association studies (GWAS).ResultsOur findings indicated that higher leucocyte count [odds ratio (OR), 1.24; 95% confidence interval (CI), 1.07 - 1.43; p = 0.0039] and lymphocyte count (OR, 1.17; 95% CI, 1.01 – 1.35; p = 0.0317) were causally associated with MS susceptibility. In addition, we also found that increase of genetically predicted natural killer T (NKT) cell count is also associated with an increase MS risk (OR, 1.24; 95% CI, 1.06 - 1.45; p = 0.0082).ConclusionsThese findings show that the genetic predisposition to higher peripheral immune cell counts can exert a causal effect on MS risk, which confirms the crucial role played by peripheral immunity in MS. Particularly, the causal association between NKT cell count and MS underscores the relevance of exploring the functional roles of NKT cells in disease pathogenesis in future.

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Section: Discussionsupporting

confidence: 91%

The Effect of Peripheral Immune Cell Counts on the Risk of Multiple Sclerosis: A Mendelian Randomization Study

Liu

Shen

et al. 2022

Front. Immunol.

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“…In contrast, Lu et al. found little evidence for a role of serum IL-6 levels in the risk of MS ( 49 ), again in line with our results. A potential explanation for the discrepancy between IL-6 signaling and IL-6 levels may be weak instrument bias, as the instruments selected for serum IL-6 levels explain solely ~1% of phenotypic variance ( 28 ) while the instruments selected for IL-6 signaling explain ~5% of phenotypic variation ( 26 ).…”

Section: Discussionsupporting

confidence: 91%

Body Mass Index, Interleukin-6 Signaling and Multiple Sclerosis: A Mendelian Randomization Study

Vandebergh¹,

Becelaere²,

Dubois³

2022

Front. Immunol.

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ObjectivesWe explored whether genetically predicted increased body mass index (BMI) modulates multiple sclerosis (MS) risk through interleukin-6 (IL-6) signaling.MethodsWe performed a two-sample Mendelian randomization (MR) study using multiple genome-wide association studies (GWAS) datasets for BMI, IL-6 signaling, IL-6 levels and c-reactive protein (CRP) levels as exposures and estimated their effects on risk of MS from GWAS data from the International Multiple Sclerosis Genetics Consortium (IMSGC) in 14,802 MS cases and 26,703 controls.ResultsIn univariable MR analyses, genetically predicted increased BMI and IL-6 signaling were associated with higher risk of MS (BMI: odds ratio (OR) = 1.30, 95% confidence interval (CI) = 1.15-1.47,p= 3.76 × 10-5; IL-6 signaling: OR = 1.51, 95% CI = 1.11-2.04,p= 0.01). Furthermore, higher BMI was associated with increased IL-6 signaling (β = 0.37, 95% CI = 0.32,0.41,p= 1.58 × 10-65). In multivariable MR analyses, the effect of IL-6 signaling on MS risk remained after adjusting for BMI (OR = 1.36, 95% CI = 1.11-1.68,p= 0.003) and higher BMI remained associated with an increased risk for MS after adjustment for IL-6 signaling (OR = 1.16, 95% CI =1.00-1.34,p= 0.046). The proportion of the effect of BMI on MS mediated by IL-6 signaling corresponded to 43% (95% CI = 25%-54%). In contrast to IL-6 signaling, there was little evidence for an effect of serum IL-6 levels or CRP levels on risk of MS.ConclusionIn this study, we identified IL-6 signaling as a major mediator of the association between BMI and risk of MS. Further explorations of pathways underlying the association between BMI and MS are required and will, together with our findings, improve the understanding of MS biology and potentially lead to improved opportunities for targeted prevention strategies.

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“…Nevertheless, the specific role of sTREM2 in the pathogenesis of MS remains to be further clarified. Besides, current MR studies have suggested a causal relationship between inflammatory and immune factors, such as CCL2, NFKB1 [ 44 ], IL2Rα [ 45 ] and the predisposition to MS, which further indicates that the disorder of inflammatory and immune processes may exert a significant impact on the development of MS, considering the important role of microglia. Yet, the multifactorial pathogenesis of MS requires much more studies to be addressed.…”

Section: Discussionmentioning

confidence: 99%

CSF sTREM2 in neurological diseases: a two-sample Mendelian randomization study

Dong

Zhou

Tang

et al. 2022

J Neuroinflammation

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Background Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in cerebrospinal fluid (CSF) has been described as a biomarker for microglial activation, which were observed increased in a variety of neurological disorders. Objective Our objective was to explore whether genetically determined CSF sTREM2 levels are causally associated with different neurological diseases by conducting a two-sample Mendelian randomization (MR) study. Methods Single nucleotide polymorphisms significantly associated with CSF sTREM2 levels were selected as instrumental variables to estimate the causal effects on clinically common neurological diseases, including stroke, Alzheimer’s diseases, Parkinson’s diseases, amyotrophic lateral sclerosis, multiple sclerosis, and epilepsy and their subtypes. Summary-level statistics of both exposure and outcomes were applied in an MR framework. Results Genetically predicted per 1 pg/dL increase of CSF sTREM2 levels was associated with higher risk of multiple sclerosis (OR = 1.038, 95%CI = 1.014–1.064, p = 0.002). Null association was found in risk of other included neurological disorders. Conclusions These findings provide support for a potential causal relationship between elevated CSF sTREM2 levels and higher risk of multiple sclerosis.

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Circulating Interleukins and Risk of Multiple Sclerosis: A Mendelian Randomization Study

Cited by 20 publications

References 44 publications

The Effect of Peripheral Immune Cell Counts on the Risk of Multiple Sclerosis: A Mendelian Randomization Study

The Effect of Peripheral Immune Cell Counts on the Risk of Multiple Sclerosis: A Mendelian Randomization Study

Body Mass Index, Interleukin-6 Signaling and Multiple Sclerosis: A Mendelian Randomization Study

CSF sTREM2 in neurological diseases: a two-sample Mendelian randomization study

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